Chronic Obstructive Pulmonary Disease (COPD) is a major unmet medical need in the United States that affects nearly 16 million Americans; yet, there are no current therapeutic treatments to halt disease progression. Cigarette smoking is the primary risk factor for COPD, which is characterized by excessive inflammation and airflow obstruction of the lung. Although inflammation is causally related to the initiation and progression of COPD, the mechanisms that underlie the associated inflammatory responses are poorly understood, impeding the development of novel therapeutics. Cigarette smoke (CS) exposure leads to the generation of oxidant stress by affecting mitochondrial function and thereby resulting in a pro-inflammatory state. The factors affecting mitochondrial health have important roles in inflammation and CS-induced COPD. In this context, we have identified Mitogen activated protein Kinase Kinase 3 (MKK3) as a negative regulator of mitochondrial health. MKK3 is a component of the innate immune response pathway and MKK3 deficient mice and cells exhibit both protection against inflammatory injury and improved mitochondrial function. We also determined that the degree of dysfunctional mitochondrial clearance through mitophagy (a cellular homeostatic mechanism to maintain a pool of healthy mitochondria) in the lungs is a major determinant of survival against oxidant- and inflammation-induced injury. Our studies show that MKK3 deletion leads to the upregulation of Parkin, a key mitophagy protein, and results in increased mitophagy and a higher pool of healthy mitochondria. Our preliminary studies of CS exposure show attenuated inflammation and mitochondrial dysfunction in MKK3-/- mice. Additionally, MKK3-/- macrophages are protected against cigarette smoke extract (CSE)-induced oxidant generation, mitochondrial dysfunction, and inflammation. Hence, we believe that targeting MKK3 could have substantial therapeutic effects in CS-induced COPD. Thus, our hypothesis is that the inhibition of MKK3 will protect against CS-induced COPD via increases in Parkin- mediated mitophagy. Studies will be conducted to elucidate the mechanism by which MKK3 regulates Parkin-mediated mitophagy and to establish the role of the MKK3-Parkin axis in the development of COPD. Translational studies with human peripheral blood mononuclear cells (PBMC) will be performed to correlate MKK3 expression and mitochondrial dysfunction to COPD. Further, proof-of-concept studies using MKK3 inhibitors as therapeutics to rescue mitochondrial dysfunction in PBMCs from COPD patients will be performed. The proposed studies will expand our basic understanding of the molecular and cellular aspects of COPD and thereby address a previously unmet need for the treatment of a major public health problem.